Maternal Genetic Variation Accounts in Part for the Associations of Maternal Size during Pregnancy with Offspring Cardiometabolic Risk in Adulthood

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Abstract

Background

Maternal pre-pregnancy body-mass index (ppBMI) and gestational weight gain (GWG) are associated with cardiometabolic risk (CMR) traits in the offspring. The extent to which maternal genetic variation accounts for these associations is unknown.

Methods/Results

In 1249 mother-offspring pairs recruited from the Jerusalem Perinatal Study, we used archival data to characterize ppBMI and GWG and follow-up data from offspring to assess CMR, including body mass index (BMI), waist circumference, glucose, insulin, blood pressure, and lipid levels, at an average age of 32. Maternal genetic risk scores (GRS) were created using a subset of SNPs most predictive of ppBMI, GWG, and each CMR trait, selected among 1384 single-nucleotide polymorphisms (SNPs) characterizing variation in 170 candidate genes potentially related to fetal development and/or metabolic risk. We fit linear regression models to examine the associations of ppBMI and GWG with CMR traits with and without adjustment for GRS. Compared to unadjusted models, the coefficient for the association of a one-standard-deviation (SD) difference in GWG and offspring BMI decreased by 41% (95%CI −81%, −11%) from 0.847 to 0.503 and the coefficient for a 1SD difference in GWG and WC decreased by 63% (95%CI −318%, −11%) from 1.196 to 0.443. For other traits, there were no statistically significant changes in the coefficients for GWG with adjustment for GRS. None of the associations of ppBMI with CMR traits were significantly altered by adjustment for GRS.

Conclusions

Maternal genetic variation may account in part for associations of GWG with offspring BMI and WC in young adults.

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Most cited references 19

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Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates.

Frances M. Williams, K. Grove, Ryan Smith … (2009)

Maternal obesity is thought to increase the offspring's risk of juvenile obesity and metabolic diseases; however, the mechanism(s) whereby excess maternal nutrition affects fetal development remain poorly understood. Here, we investigated in nonhuman primates the effect of chronic high-fat diet (HFD) on the development of fetal metabolic systems. We found that fetal offspring from both lean and obese mothers chronically consuming a HFD had a 3-fold increase in liver triglycerides (TGs). In addition, fetal offspring from HFD-fed mothers (O-HFD) showed increased evidence of hepatic oxidative stress early in the third trimester, consistent with the development of nonalcoholic fatty liver disease (NAFLD). O-HFD animals also exhibited elevated hepatic expression of gluconeogenic enzymes and transcription factors. Furthermore, fetal glycerol levels were 2-fold higher in O-HFD animals than in control fetal offspring and correlated with maternal levels. The increased fetal hepatic TG levels persisted at P180, concurrent with a 2-fold increase in percent body fat. Importantly, reversing the maternal HFD to a low-fat diet during a subsequent pregnancy improved fetal hepatic TG levels and partially normalized gluconeogenic enzyme expression, without changing maternal body weight. These results suggest that a developing fetus is highly vulnerable to excess lipids, independent of maternal diabetes and/or obesity, and that exposure to this may increase the risk of pediatric NAFLD.

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Impact of maternal obesity on offspring obesity and cardiometabolic disease risk.

Paul Reynolds, Amanda J Drake (2010)

The prevalence of obesity among pregnant women is increasing. In addition to the short-term complications of obesity during pregnancy in both mother and child, it is now recognised that maternal obesity has long-term adverse outcomes for the health of her offspring in later life. Evidence from both animal and human studies indicates that maternal obesity increases the risk for the offspring in developing obesity and altering body composition in child- and adulthood and, additionally, it also has an impact on the offspring's cardiometabolic health with dysregulation of metabolism including glucose/insulin homoeostasis, and development of hypertension and vascular dysfunction. Potential mechanisms include effects on the development and function of adipose tissue, pancreas, muscle, liver, the vasculature and the brain. Further studies are required to elucidate the mechanisms underpinning the programming of disease risk in the offspring as a consequence of maternal obesity. The ultimate aim is to identify potential targets, which may be amenable to prevention or early intervention in order to improve the health of this and future generations.

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Associations of maternal prepregnancy body mass index and gestational weight gain with adult offspring cardiometabolic risk factors: the Jerusalem Perinatal Family Follow-up Study.

Hagit Hochner, Yechiel Friedlander, Ronit Calderon-Margalit … (2012)

Accumulating evidence demonstrates that both maternal prepregnancy body mass index (mppBMI) and gestational weight gain (GWG) are associated with adult offspring adiposity. However, whether these maternal attributes are related to other cardiometabolic risk factors in adulthood has not been comprehensively studied. We used a birth cohort of 1400 young adults born in Jerusalem who had extensive archival data and clinical information at 32 years of age to prospectively examine the associations of mppBMI and GWG with adiposity and related cardiometabolic outcomes. Greater mppBMI, independently of GWG and confounders, was significantly associated with higher offspring BMI, waist circumference, systolic and diastolic blood pressures, insulin, and triglycerides and with lower high-density lipoprotein cholesterol. For example, the effect sizes were translated to nearly 5 kg/m(2) higher mean BMI, 8.4 cm higher waist circumference, 0.13 mmol/L (11.4 mg/dL) higher triglycerides, and 0.10 mmol/L (3.8 mg/dL) lower high-density lipoprotein cholesterol among offspring of mothers within the upper mppBMI quartile (mppBMI >26.4 kg/m(2)) compared with the lower quartile (mppBMI 14 kg) and lower (GWG <9 kg) quartiles of GWG were compared. Further adjustment for offspring adiposity attenuated the observed associations to the null. Maternal size both before and during pregnancy is associated with cardiometabolic risk factors in young adult offspring. The associations appear to be driven mainly by offspring adiposity. Future studies that explore mechanisms underlying the intergenerational cycle of obesity are warranted to identify potentially novel targets for cardiometabolic risk-reduction interventions.

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Author and article information

Contributors

Guoying Wang: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 26 March 2014

Volume: 9

Issue: 3

Electronic Location Identifier: e91835

Affiliations

[1 ]Department of Epidemiology, University of Washington, Seattle, Washington, United States of America

[2 ]Department of Medicine, University of Washington, Seattle, Washington, United States of America

[3 ]Braun School of Public Health, Hebrew University-Hadassah Medical Center, Jerusalem, Israel

[4 ]Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, United States of America

[5 ]Department of Statistics, University of Auckland, Auckland, New Zealand

[6 ]Department of Human Genetics, Hebrew University-Hadassah Medical Center, Jerusalem, Israel

[7 ]Institute of Human Genetics, University of California San Francisco, San Francisco, California, United States of America

[8 ]Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, United States of America

[9 ]Department of Dermatology, University of California San Francisco, San Francisco, California, United States of America

Johns Hopkins Bloomberg School of Public Health, United States of America

Author notes

* E-mail: lwander@ 123456u.washington.edu

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: HH DAE TL GML AB BS OM VM SH PYK DSS YF. Performed the experiments: SH PYK. Analyzed the data: PLW CMS. Wrote the paper: PLW HH CMS DAE DSS YF.

Article

Publisher ID: PONE-D-13-31024

DOI: 10.1371/journal.pone.0091835

PMC ID: 3966761

PubMed ID: 24670385

SO-VID: dc8f64e9-0268-4933-8648-5bc32fec0526

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 30 July 2013

Date accepted : 12 February 2014

Page count

Pages: 7

Funding

This research was supported by the T32-HL07902 training grant and R01-HL088884 from the National Heart, Lung, and Blood Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Maternal Genetic Variation Accounts in Part for the Associations of Maternal Size during Pregnancy with Offspring Cardiometabolic Risk in Adulthood

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Abstract

Background

Methods/Results

Conclusions

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PLOS Climate

Most cited references 19

Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates.

Impact of maternal obesity on offspring obesity and cardiometabolic disease risk.

Associations of maternal prepregnancy body mass index and gestational weight gain with adult offspring cardiometabolic risk factors: the Jerusalem Perinatal Family Follow-up Study.

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